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Casting a glance at CD33
SAN DIEGO—Humans are unique in the animal world for many reasons, among them the fact that our lives extend far past the reproductive age, which for other species (excluding some whales) is the end of their biological necessity; having passed on the genes that allowed them to live and survive to adulthood, all other animals have fulfilled their biological imperative by reproducing. Humans, however, can still contribute after their reproductive years by passing on their knowledge to the younger generations. Recent work by a University of California, San Diego School of Medicine team focused on how certain gene variants have evolved to protect against neurodegenerative diseases and preserve the place of elders in our society.
This study was led by Dr. Ajit Varki, Distinguished Professor of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, adjunct professor at the Salk Institute for Biological Studies and co-director of the UC San Diego/Salk Center for Academic Research and Training in Anthropogeny (CARTA), along with Dr. Pascal Gagneux, associate professor of pathology and associate director of CARTA. The paper, “Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline,” appeared in the Nov. 30 issue of Proceedings of the National Academy of Sciences.
The bulk of this work focused on the gene that encodes the cluster of differentiation 33 (CD33) protein, a receptor that projects from the surface of immune cells. This receptor helps to mediate immune reactions, preventing the immune system from attacking itself and preventing unwanted inflammation. Previous work has implied that one form of CD33 can suppress accumulation of amyloid beta peptide—a contributor to late-onset Alzheimer’s disease—in the brain. In a 2014 Molecular Neurobiology paper, “CD33 in Alzheimer's disease,” it was noted that “In the brain, CD33 is mainly expressed on microglial cells. The level of CD33 was found to be increased in the AD brain, which positively correlated with amyloid plaque burden and disease severity. More importantly, CD33 led to the impairment of microglia-mediated clearance of Aβ, which resulted in the formation of amyloid plaques in the brain.”
In this recent PNAS study, when CD33 regulation in humans was compared with that of chimpanzees, the team discovered that levels of the CD33 variant that conveys protection against Alzheimer’s disease are four-fold higher in humans than in chimpanzees.
“We unexpectedly discovered that humans have evolved gene variants that can help protect the elderly from dementia,” explained Varki. “Such genes likely evolved to preserve valuable and wise grandmothers and other elders, as well as to delay or prevent the emergence of dependent individuals who could divert resources and effort away from the care of the young.”
In addition, there are human-specific variations in a number of other genes involved in the prevention of cognitive decline, including APOE. The ancestral form of this gene, APOE4, is a well-known risk factor for Alzheimer’s disease as well as cerebral vascular disease, as individuals with the APOE4 gene have been found to comprise a majority of patients with Alzheimer’s disease. However, according to this study, the gene variants APOE2 and APOE3 seem to have evolved to offer protection from dementia. All of the protective gene variants are found in Africa, predating the origin of the human species.
“When elderly people succumb to dementia, the community not only loses important sources of wisdom, accumulated knowledge and culture, but elders with even mild cognitive decline who have influential positions can harm their social groups by making flawed decisions,” Gagneux said. “Our study does not directly prove that these factors were involved in the selection of protective variants of CD33, APOE and other genes, but it is reasonable to speculate about the possibility. After all, inter-generational care of the young and information transfer is an important factor for the survival of younger kin in the group and across wider social networks or tribes.”